PROJECT SUMMARY/ABSTRACT It is now well understood that multiple growth factors impact the response of myelinated axons to demyelination. One of these growth factors, brain-derived neurotrophic factor (BDNF), has been found to elevate myelin proteins when injected directly into the corpus callosum lesion site in a cuprizone-induced model of demyelination in mice. However, administration of exogenous proteins such as BDNF to the central nervous system may prove difficult as a form of treatment. Therefore, an intriguing therapeutic approach for demyelinating diseases may be to enhance an endogenous brain source of BDNF. Previous studies have shown that the Group I and Group II metabotropic glutamate receptor (mGluR) agonist, trans-(1S,3R)-1-amino- 1,3-cyclopentanedicarboxylic acid (ACPD), enhances BDNF in primary mouse astrocyte culture. Furthermore, ACPD elevates both BDNF and myelin proteins when injected directly into the lesioned corpus callosum of mice following cuprizone-induced demyelination and the astrocyte-derived BDNF is responsible, at least in part, for effects on myelin proteins. Subsequent work suggested that ACPD acts through Group I mGluRs to elicit its effects. This is supported by the fact that the Group I mGluR agonist 2-chloro-5-hydroxyphenylglycine (CHPG), but not that Group II mGluR agonist DCGIV, increases BDNF and myelin proteins when injected directly into the lesion. Preliminary studies also suggest that BDNF and myelin proteins are elevated when CHPG is injected not only centrally, but also through the more clinically relevant route of a peripheral injection. However, the cellular mechanisms responsible for increases in myelin proteins after CHPG administration are not yet understood, nor are the functional effects of CHPG on the animal. We hypothesize that CHPG acts to promote the differentiation of oligodendrocyte lineage cells through astrocyte-derived BDNF while also enhancing behavioral recovery associated with remyelination. Aim 1A will define the effects of CHPG on the differentiation of oligodendrocyte lineage cells following a cuprizone-induced lesion. Aim 1B will determine the role of astrocyte-derived BDNF on oligodendrocyte lineage cells following CHPG treatment to a cuprizone- induced lesion. Aim 2 will investigate the effects of CHPG on behavioral deficits following cuprizone. It is our hope that this research will contribute to our understanding of how to enhance oligodendrocyte regeneration and provide a critical first step towards identifying one potential therapeutic strategy for treating demyelinating diseases. At the completion of this research and the F31 Fellowship, the Principal Investigator will be trained to conduct independent research in the fields of neurotoxicology, neuropharmacology, and neurodegenerative diseases.